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Viagra Finds a New Role: It May Shrink Enlarged
Hearts
Jan. 23, 2005 - Researchers at Johns Hopkins have
found that sildenafil citrate (Viagra), a drug used to treat erectile
dysfunction (ED) in millions of men, effectively treats enlarged hearts
in mice, stopping further muscle growth from occurring and reversing
existing growth, including the cellular and functional damage it
created.
"A larger-than-normal heart is a serious medical
condition, known as hypertrophy, and is a common feature of heart
failure that can be fatal," says study senior author and cardiologist
David Kass, M.D., a professor at The Johns Hopkins University School of
Medicine and its Heart Institute. Kass is also the Abraham and Virginia
Weiss Professor of Cardiology at Hopkins.
Sildenafil, Kass says, was the focus of his
research because it blocks or stops an enzyme, called phosphodiesterase
5 (PDE5A), involved in the breakdown of a key molecule, cyclic GMP,
which serves as a "natural brake" to stresses and overgrowth in the
heart. "We thought we could more strongly apply the brake on hypertrophy
in the heart if we used sildenafil to prevent the breakdown of cyclic
GMP," he says. The makers of the drug had no involvement in the design
or support of the research. PDE5A is also the biological pathway blocked
in the penis to prevent the relaxation of blood vessels and maintain
erections.
The Johns Hopkins findings, to be published in the
journal Nature Medicine online Jan. 23, are the first to show that
sildenafil is an effective treatment for a chronic heart condition. It
is also the first study to reveal that the enzyme pathway blocked by
sildenafil (PDE5A), never before known to play a significant role in the
heart, is active when the heart is exposed to pressure stress and
hypertrophied. The results provide some of the strongest evidence to
date that blocking the heart's adaptive response to hypertrophy does not
harm its function but, in fact, may improve it, Kass says. Already,
plans are under way by the Hopkins researchers for a multicenter trial
to test if sildenafil has the same effects on hypertrophy in humans.
In the first of several experiments, each involving
groups of 10 to 40 male mice, the Hopkins team stimulated hypertrophy
for up to nine weeks, but only by half as much in those that had also
consumed sildenafil in their food at 100 milligrams per kilogram per
day. In mice, this dose produces blood levels similar to those achieved
in humans given standard clinical doses.
The mice fed sildenafil also showed 67 percent less
muscle fibrosis, a complication that often occurs with hypertrophy, as
compared to mice that were not fed the drug. The treated mice also had
smaller hearts and improved heart function, whereas the untreated hearts
were dilated with weakened function. For all mice with hypertrophy, the
condition was surgically produced by constricting the main artery
carrying blood from the heart to create pressure stress.
In a second experiment, the researchers used the
same dose of sildenafil and examined its effects on reversing
hypertrophy that had already occurred. Initially, these mice were
exposed to pressure stress for seven to 10 days, with hearts developing
fibrosis and muscle growth by nearly 65 percent. After two weeks of
therapy, fibrosis and muscle growth almost completely disappeared. In
mice that did not have therapy, hearts continued to get bigger.
In a surprising result, the researchers found that
heart function, as measured by pressure-volume analysis of the muscle's
ability to contract and pump blood, actually improved after hypertrophy
had been stopped and treated. While researchers previously thought that
hypertrophy was an adaptive response to pressure stress, the functional
gains lasted despite the heart's continued exposure to high blood
pressure. Improvements were seen in more than 10 measures of heart
function, including heart relaxation, cardiac output and heart
contractility, which increased by nearly 40 percent. These improvements
were seen even when therapy was deferred and started two weeks after
hypertrophy had already developed.
"This study shows that sildenafil can make
hypertrophy go away," says Kass. "Its effects can be both stopped in
their tracks and reversed. Overall, the results provide a better
understanding of the biological pathways involved in hypertrophy and
heart dilation, leading contributors to heart failure. They suggest
possible therapies in the future, including sildenafil, which has the
added benefit of already being studied as safe and effective for another
medical condition."
"It also suggests that less but, perhaps, the right
kind of hypertrophy can be good for the heart. However, more study is
required before we fully understand the benefits of sildenafil on the
heart."
Analysis of several enzymes known to play a major
role in triggering hypertrophy, including calcineurin and Akt, showed
increased activity and amounts in the hypertrophied heart, but after
treatment with sildenafil, their levels returned back to normal levels.
Funding for this study, which took three years to
complete, was provided entirely by the National Institutes of Health (NIH),
American Heart Association, Peter Belfer Laboratory Foundation, American
Physiological Society, and the Bernard Family Foundation. The lead
Hopkins researchers who took part in this study were Eiki Takimoto,
M.D., Ph.D.; Hunter Champion, M.D., Ph.D.; and Maxiang Li, M.D., Ph.D.
Other researchers who took part in this study were Diego Belardi, M.D.;
Shuxun Ren, M.D.; E. Rene Rodriguez, M.D.; Djahida Bedja, B.S.; Kathleen
Gabrielson, D.V.M., Ph.D.; and Yibin Wang, Ph.D.
Cardiac hypertrophy commonly develops from high
blood pressure, which forces the heart to pump harder to circulate blood
throughout the body. According to the latest statistics from the
American Heart Association, in 2002, 65 million Americans have high
blood pressure (defined as systolic pressure of 140 millimeters of
mercury or greater, and/or a diastolic pressure of 90 millimeters of
mercury or greater, taking antihypertensive medication or being told at
least twice by a physician or other health professional that they have
high blood pressure). Patients that develop hypertrophy have two to
three times the risk of suffering cardiovascular disease, including
heart failure and sudden cardiac death.
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